Choline salicylate compositions

ABSTRACT

CHOLINE SALICYLATE-SILANIZED SILICON DIOXIDE A STABLE SOLID, NON-HYDROSCOPIC COMPOSITION POSSESSING THE FULL SPECTRUM OG ANALGESIC,ANTI-PYRETIC AND ANTI-INFLAMMATORY PROPERTIES OF CHOLINE SILICYLATE IS PREPARED BY REACTING A CHOLINE ION WITH A SALICYLATE ION AND THEN COMBINING WITH SILANIZED SILICON DIOXIDE IN THE PRESENCE OF AN INERT ANHYDROUS SOLVENT TO FORM THE NEW COMPOSITION. SOLID PHARMACEUTICAL DOSAGE FORMS ARE PREPARED WITH THE NEW COMPOSITION WHICH ARE USEFUL IN THE TREATMENT OF MUSCULO-SKELETAL DISEASE, THE RELIEF OF PAIN AND THE LOWERING OF FEVER IN HUMANS AND ANIMALS. A METHOD FOR INCREASING THE CONCENTRATION OF BLOOD SALICYLATE ION THROUGH THE ORAL ADMINISTRATIONOF THE AFORESAID CHOLINE SALICYLATE-SILANIZED SILICON DIOXIDE AND PHARMACEUTICAL COMPOSITION CONSISTING THE SAME, IS PRESENTED.

United States Patent CHOLINE SALICYLATE COMPOSITIONS Walter-Thomas. Swimm Darien, Conn.,,assignor to The f Purdue, Frederick Company, Yonkers, NY. N0 Drawing. Filed Nov. 6, 1972, Ser. No. 303,920 Int. Cl.'C07f 7/08, 7/18 U.S.'Cl:"260-448.2 N I 6 Claims ABSTRACT OF THE DISCLOSURE Choline salicylate-silanizedsilicon dioxide'a stable solid, non-hygroscopic:composition possessing the full spectrum of analgesic, anti-pyretic and anti-inflammatory properties ofcholine silicylate is prepared by reaching a choline ion with a salicylate ion and then combining with silanized silicon dioxide in the presence of an inert anhydrous solvent to form the new composition. Solid pharamaceutical dosage forms are prepared with thenew composition which are useful in the treatment of musculo-skeletal disease, therelief of pain and the lowering-of fever in humans and animals. A method for increasing the concentration of blood salicylate ion through the oral administration of the aforesaid choline salicylate-silanized silicon dioxide and pharmaceutical composition containing the same, is presented.

The present invention vrelates to solid therapeutic salicylate-containing compositions; a method for their preparation and a method for their use in achieving a therapeutic effect. In particular it is concerned with a solid pharmaceutical compound comprising choline salicylate and silanized silicondioxide; a method for its preparation, pharmaceutical compositions containingthe same, and a method for their use in achieving a therapeutic effect. It is anobject of the present invention to describe a solid pharmaceutical composition, choline salicylatesilanized silicon dioxide and capsules, tablets and granules containing the same, which are stable and non-hygroscopic when exposed to the atmosphere for prolonged periods, and which are useful as an analgesic, antipyretic and antiinflammatory'agent. 1

Choline salicylate is a well defined crystalline compound melting at 49.5 C. to 50.5" C. and has 'a molecular weight of 241.28. Themethod for its preparation and its properties are described in U.S. Pat.--.3,069,321, patented Dec. 18, 1962. A 10 percent aqueous solution of choline salicylate (w./w.) has a pH of 6.75 and it does not liberate free salicylate acid above pH 3.5. While choline salicylate is extremely soluble in water, alcohol, acetone and glycerin, it is insoluble in anhydrous ether, benzene and petroleum ether.

Choline salicylate has been established to be a desirable analgesic-antipyretic compound and has noteworthy pharmacologic and therapeutic properties useful in the treatment of 'a broad range of musculo-skeletal disorders as well as to provide desirable ,pain relief and antipyresis. Choline salicylate has been shown topossess desirable anti-inflammatory properties and to be useful for administration by oral, rectal, topical and, parenteral routes.

Despite its desirable pharmacologic and therapeutic spectrum, choline salicylate has certain inherent limitations. in that it is extremely hygroscopic so that the preparation of solid pharmaceutical dosage forms are not readily accomplished. Thus, when crystalline choline salicylate melting at 49.'5 C. to 50.5 C. is exposed to. even the trace moisture in the atmosphere, it liquifies and after absorption of water, it is virtually impossible to recon stitute .into the dry crystalline form. This undesirable hygroscopic property prevents the preparation of solid pharmaceutical dosage forms; as 'for example, capsules,

essentially liquid; dosage-forms. 1 a

1 of the traveler or for convenient use by ambulatory, outpatients during the day. Another limitation of the liquid dosage .form is the difliculty in achieving a palatable, pleasing taste to mask the inherent characteristic, noxious fishy taste and odor of choline compounds. When such flavoring has been accomplished for certain preparations, it is usually the result of costly developmental research effort, utilizing expensive flavoring agents.

While much research has been expended in attempting to achieve a stable solid non-hygroscopic form of choline salicylate, the results have been generally wanting. Thus, US. Pat. 3,297,529 (patented Jan. 10, 1967) describes a solid choline salicylate stabilized by the addition of magnesium sulfate to form a non-hygroscopic mixture. The composition described in the aforesaid U.S. Pat. 3,297,529 is a solid product varying in composition of from 25 percent to 80 percent choline salicylate and contains from 20 percent to 75 percent of magnesium sulfate. The mixture is described as having varying properties as a function of the ratio of choline salicylate and magnesium sulfate used. Magnesium sulfate is a well known cathartic agent and thereby adds an unwanted cathartic response to the salicylate preparations. It is well known that patients utilizing salicylate therapy for musculo-skeletal disorders require large doses of the salicylate preparation for extended periods of time and in these cases and for these patients the laxative efiect resulting from administration of magnesium sulfate would be a serious therapeutic limitation.

Another attempt to avoid the limitation of hygroscopic properties of choline salicylate is found in U.S. Pat. 3,326,760, patented June 20, 1967, wherein choline salicylate was. found to combine with polygalacturonic acid to result in free-flowing, granular powder which was stable and non-hygroscopic. However, choline salicylate polygalacturonate is a new compound which has a different 1 composition is without a sharp melting point, but shows oxide-as representing the'same chemical compound. Silandecomposition beginning at 245 C. and is non-hygroscopic, being stable under the usual storage conditions for prolonged periods of time. ,When exposed to the atmosphere in open plates .for a period of three months at ambient room temperature, thenew composition retain itsfree-flcwing, solid powder characteristics in contrast to crystalline choline salicylate which liquifies in a matter of hours when exposed to the atmosphere.

Silanized silicon dioxide is a hydrophobic substance comprising trimethylsilyl silicon dioxide in intimate, homogeneous combination and is known in the trade as Silanox, a product distributed by the Cabot Corporation of Boston, Mass. Those versed in the artprefer the term silanized silicon dioxide to describe trimethylsilyl silicon dioxide, although the trade name Silanox is also widely utilized for this compound. Thus, wherever'the term silanized'silicon dioxide appears in the present description'and also wherever the term .Silanox is used,'these terms may be read interchangeably to mean trimethylsilylsilicon di 3 ized silicon dioxide, or trimethylsilylsilicon dioxide, or Silanox, is a homogeneous chemical compound with certain chemical composition, having characteristic properties which serve to distinguish and identify this compound.

Silane, a member of the silicon class of chemical compounds, contributes an inherent hydrophobicity and lipophilicity to a silicon dioxide particle, which at the same time has been reduced in particle size to provide an enormous surface area. The basic silicon dioxide particle is produced by the hydrolysis of silicon tetra-chloride in a flame process, to result in a particle that is non-porous and amorphous, and of high purity possessing an enormous specific surface area. The primary particle is about 7 millimicrons in diameter and these particles are concentrated into long-branch micron-size aggregates.

The silicon dioxide particle is normally hydrophilic due to a large number of hydroxyl groups present on its surface and it is this property which is eliminated as a result of the chemical reaction between silicon dioxide and silane, whereby hydrocarbon groups replace many of the hydroxyl groups of the silicon dioxide. Silane is a member of the silicon family containing aliphatic substitution of the hydroxyl group. In the present instance, trimethylsilyl, a silane, is reacted with silicon dioxide to form trimethylsilylsilicon dioxide, or silanized silicon dioxide. The newly formed chemical bond between the silane moiety and silicon dioxide are not responsive to high temperature degradation or solvent extraction. The silanized silicon dioxide particle has been shown to have an amorphorus structure by X-ray analysis; a specific gravity of 2.2, and a pH of between pH 8 and pH 10. Laboratory studies have indicated that this compound to be virtually non-toxic when ingested and it does not in general act as a skin-irritant when topically applied.

The new composition, choline salicylate-silanized silicon dioxide is prepared under anhydrous conditions. A preferred method of preparation utilizes equimolar concentrations of choline chloride and sodium salicylate, suspended in acetone which are mixed and refluxed for approximately four hours. After cooling and filtering, silanized silicon dioxide, equivalent in weight to the amount of choline salicylate formed, is added to the filtrate and stirred. An equal volume of petroleum ether is then added and the whole allowed to stand overnight. The solvent is removed and the formed choline salicylate-silanized silicon dioxide is dried at room temperature, under low vacuum, until free of solvent. The resulting formed product is obtained in a better than 90 percent yield and is a stable, solid white granular powder without a definite melting point but showing decomposition at 245 C.

While the preferred ratio of silanized silicon dioxide moiety to choline salicylate moiety is equal parts by weight of silanized silicon dioxide and choline salicylate, an optional range of the ratio of silanized silicon dioxide to choline salicylate is between 30 and 140 parts by weight of silanized silicon dioxide for each 100 parts by weight of choline salicylate. In certain instances and for special purposes a greater or lesser quantity of silanized silicon dioxide for each part of choline salicylate may be used to obtain a solid mass suitable for further pharmaceutical manufacture or even for patient administration as is.

The new formed choline salicylate-silanized silicon dioxide composition possesses all of the pharmacologic and therapeutic properties of choline salicylate and may be used in therapy of humans and animals as a means for increasing theg lood level of salicylate ion. Furthermore, it may be utilized with particular advantage whenever salicylate therapy is indicated as an analgesic and antipyretic agent, as well as an anti-inflammatory compound.

After the oral administration of the new composition to humans and animals, there is a rapid systemic absorption of choline salicylate to significantly increase the blood level of salicylate ion. The oral administration of the new composition may be fa ilitated through pharmaceutically com- 4 pounding the new stable solid choline salicylate-Silan0x into tablets, capsules and granule dosage forms although the choline salicylate-Silanox compound may be administered directly to the human or animal patient.

When a tablet dosage form is desired, then the freeflowing solid powder choline salicylate-Silanox composition is mixed with a suitable binding agent and tablet lubricant and compressed into tablets of desired size and shape. Capsules are prepared by filling approprite gelatin capsules with a new composition. Granules are prepared by mixing the new composition with a diluent and a granulating agent and passing the mass through a No. 8 U8. standard mesh sieve and drying the resultant granule. Suitable color and flavoring materials may be added to each of the respective forms, if desired.

The unit dosge concentration of choline salicylate-silanized silicon dioxide utilized to prepare the respective solid pharmaceutical dosage forms will vary according to their intended use.

A preferred concentration of active ingredient in a unit dosage form, as for example, one tablet, one capsule or one teaspoon (3 grams) of granules, is 875 mg. of choline salicylate-silanized silicon dioxide unit dosage form, said formed active ingredient containing equal parts by weight of choline salicylate and silanized silicon dioxide, which concentration is equivalent in salicylate content to the conventional 5 grain aspirin tablet. However, from A to /2 this quantity of active compound may be desired for the preparation of childrens tablets, capsules and granules. This dosage may also be desired for geriatric use or for use in the debilitated patient.

For special therapeutic uses, as for example in the treatment of chronic musculo-skeletal disease or in arthritic and rheumatic conditions, the concentration of active ingredient per unit dosage form may be desired to be increased to facilitate the administration of the large quantities of salicylate compound ordinarily utilized. Special tablets and granules containing twice the ordinary unit dose quantity, or 1750 mg. of choline salicylate-silanized silicon dioxide-Silanox compound equivalent to 10 grains of aspirin in salicylate content may be utilized. Granules containing even higher concentration of active ingredient per unit dosage form to be the equivalent of three 5 grain aspirin tablets per unit dose may be prepared with the new composition.

The new composition, choline salicylate-silanized silicon dioxide, is particularly suitable to the preparation of an effervescent dosage form, i.e., granules or tablets. The deliquescent properties and extreme hygroscopicity of choline salicylates has hitherto made it impossible to prepare any effervescent dosage form containing this desirable active ingredient. It is generally accepted that an efiervescent salicylate preparation in either the granule or tablet dose form, constitutes a highly desirable therapeutic agent since it combines the gastro-intestinal soothing and buffering properties of the effervescent carrier with the therapeutic properties of the salicylate compound. Such effervescent preparations, to wit, tablets or granules, were hitherto unknown to contain choline salicylate and may be prepared utilizing the new choline salicylate-silanized silicon dioxide-silane compound thereby providing the full spectrum of advantageous properties of choline salicylate with those of the elfervescent carrier.

The daily dose of new active compound administered in therapy will generally follow the equivalent salicylate requirements determined for the particular human or animal patient being treated. The daily dosage therefore may range from 875 mg. of active compound per day to as high as 10.5 gmper day. Generally, the administration of unit dose containing 875 mg. of active compound to a human or animal from one to six times daily, will be suflicient to achieve the desired analgesic, antipyretic and'anti-inflammatory action for a majority of patients. It is recognized, however that some human or animal-patients will-require a greaterquantity-and others a lesser quantity of active compound per day depending upon the severity of disease present, thegeneral physical status of the patient and the age 'of said patient.

The following examples illustrate the invention bu isnot intended to be limited thereto. I

EXAMPLE 1 In a suitable container 261.8 gm. o f choline chloride is suspended'in fourliters. of acetone. To this susptension refluxed for fourhou'rs while stirring. The rnixtur'e is allowed to cool; the sodium chloride precipitate removed and 454 gms. of trimethylsilyl silicon dioxide (Silanox) is'added to the liquid and the whole stirred forone hour,

and set aside overnight. The solid formed cholinesalicy late-Silanox or cholinesalicylate silanized siliconf'dioxide composition is separated from the supernatantsolvent and dried under low vacuum. The resultant formed prod not is a-free-fiowing white powder obtained in greater than 90 percent yield. The formed product assays to contain between 95 percent and 100 percent of the theoretical quantity of choline moiety and between 100 percent and 101 percent of the theoretical quantity of salicylate moiety. The pH of 5 percent (w./w.) in water slurry is pH"7.7. The new composition has a faint, sweet odor and a characteristic taste. It is insoluble in water, alcohol and the common organic solvents. The new compound is stable when stored at room temperature for prolonged periods of time. When exposed to the atmosphere in an open dish for a period of up to three months, it retains its solid, free-flowing, powder characteristics and is not hygroscopic.

' EXAMPLE 2 To 241.28 gm. of choline salicylate dissolved in two liters of acetone is added 241.28 gm. of trimethylsilyl silicon dioxide. The mixture is stirred and two .liters of anhydrous petroleum other are added. The whole is set aside for a period of at least 12 hours. The solvent is removed and the residue dried at room temperature to obtain the formed choline salicylate-Silanox composition which corresponds in every way to the product obtained as a result of Example 1 above.

EXAMPLE 3 'In a suitable vessel containing three liters of anhydrous ethanol is added one gram molecular weight of choline base and one gram molecular Weight of salicylic acid. The mixture is stirred, refluxed for four hours and cooled and 242 gms. of trimethylsilyl silicon dioxide are added and the whole stirred for one hour. Three liters 'of anhydrous ether are added and the mixture is set aside overnight. The solid precipitate is separated from the solvent and air-dried to obtain the formed choline salicylate Silanox composition having identical properties-as that obtained as a result of Example 1 above.

EXAMPLE 4 In a suitable vessel containing one gram molecular weight of choline bicarbonate in anhydrous isopropanol, is added one gram molecular weight of salicylic acid in small increments. The addition of each increment of salicylic acid is made after the ebullition of carbon dioxide ceases. The mixture is stirred, refluxed for a period of at least One hour; cooled to room temperature and 242 gm. of Silanox is added. One liter of anhydrous chloroform is added and the mixture is set aside for a period of at least 8 hours. The formed precipitate is separated from the supernatant liquid and dried. The resulting formed choline salicylate-Silanox compound is identical to that obtained as a result of Example 1 above.

Equimolar quantities of choline carbonate may be substituted for the choline bicarbonate described above; the remainder of the steps being the same and the resultant product is the same as that obtained as a result of Ex- "l" l'abovei" -EXAMPLE 5 place of the acetone used as described above, there 1 stituted in equal amounts an anhydrous alcohol of ulaTtOH wherein R is an alkyl group of from one 7 carbon atoms in chain length.

lln place o f fi the petroleum ether utilized in Example 1 above; there. may be substituted equivalent amounts of v anhydrousether, benzene, chloroform or mixtures of the is added 102.2 gm. of sodium sal cylate and the whole same., a

Iniplace of the choline chloride utilized as described above' there may be substituted choline bromide, choline iodide, choline sulfate, choline nitrate, choline citrate, choline carbonate, choline bicarbonate, choline formate, choline bisulfate, choline sulfite, choline bisulfite, and choline, acetate.

. I 1 1'p 1 ace of the sodium salicylate utilized as described above, there may be substituted in equal molecular quantities a metallic salicylate salt capable of reacting with said choline 'salts ,to form choline salicylate. Such metallic salicylate salts as potassium salicylate, lithium salicylate, calcium salicylate, magnesium salicylate, strontium salicylate, zinc. and aluminum salicylate are useful in the above described process. The remainder of the steps being the same and the formed product obtained is identical to that resulting in Example 1 above.

1 EXAMPLE 6 4 ,Wh"en it is desired to prepare tablets of the formed new composition choline salicylate-Silanox, then 875 gm. of

the newcomposition obtained as a result of Examples 1 to 5 above, is mixed with diluted absolute alcohol containing a suitable binder such as povidone, starch gelatin,

and acacia and passed through a No. 16 US. standard mesh screen. The granules are dried, lubricated and compressed into tablets of suitable size and shape so that each tablet contains 875 mg. of the formed choline salicylate-Silanox composition which is equivalent in salicylate content of 5 grains of aspirin. By appropriate adjustment of the .CQHCBntration of choline salicylate-Silanox compositioi'i" stable pharmaceutical tablets, equivalent to.2.5 grains ,of aspirin or. containing4375 mg. of the formed composition tablet and 1.25 grains ofaspirin-equiva: lent or containing 218.75 ,mg. of the formed composition per tablet, the tablets are stable and non-hygroscopic when stored for prolonged periods of time. p

I 'An alternate: procedure Ito, prepare tablets with the formed newcomposition, trimethylsilylsilicone dioxide; choline salicylate is to directly compress an appropriate quantity ofthe active ingredient irito tablets of suitable shape so that the individualltablets. containla therapeutically sufficient quantity to achieve, their desired analgesic,' antipyretio or anti-inflammatory effect when m'i nisteredtoahuman or animalpatient.

' EXAMPLE 7 n Qapstiles containing the. formed new composition are preparedibydilling. into'appropriate gelatin capsules of suitable size and shape the'formed new composition obtained as a result of Example 1 to 5 above so that each capsule contains 875 mg. of the formed new composition whencapsules containing an equivalent 5 grains of aspirin aredesired, or 437.5 mg. of the formed composition per capsule when capsules, equivalent to 2.5 grains of aspirin are desired, or 218.75 mg. of the formed new composition per capsule when capsules equivalent'to 1.25 grains of aspirin are desired. The capsules are stable under the ordinary conditions of storage and are non-hygrw scopic.

EXAMPLE 8 Granules are prepared by mixing a suitable quantity of the formed new composition with suflicient quantity of diluent and binders to provide a therapeutically suflicient amount of the formed new active compound in each teajustment of the amount of active material, granules may be prepared to contain the new compound in concentration equivalent of grains of aspirin per unit dose (one teaspoonful of granule) or 1750 mg. of active material per teaspoonful. Granules are stable and non-hygroscopic when stored under the usual storage conditions.

EXAMPLE 9 When it is desired to utilize the new choline salicylate- Silanox compound in therapy then a therapeutically sulficient quantity of the aforesaid compound may beorally administered to a human or animal, or a suitablepharmaceutical dosage form, as for example, a tablet, capsule, or granular, or suspension containing the aforesaid new compound as the active ingredient, is administered by the oral route to a human or animal. While the new compound,

per se, or a tablet, capsule or granule containing the new compound is ingested in the solid form, or under certain circumstances, suspended in water to be swallowed directly, the effervescent tablet, and the effervescent powder require prior admixture with water or other suitable fluid (i.e., fruit juices) to permit eifervescence, in order to ob: tain the full beneficial effect of the respective effervescent preparation. A

Irrespective of the therapeutic dosage form preferred to administer the active compound, the amount of active compound administered per day to a human or animal will depend upon the nature of the disease being treated and the particular needs of the patient. While it may be sufficient to administer a single dose containing 875 mg.

of the formed new active compound to provide analgesic relief to a patient presenting a complaint of simple headache, larger quantities will be required for those patients with the more complex musculo-skeletal disorders, as for example, rheumatic and arthritic disease, and these may range as high as 20 gmgof the new compoundfper day. Clinicians conducting the well known therapeutic regimens utilizing salicylate-containing medications, will adjust the dosage, to the patients requirements, and generally the medication will be administered by the oral route in divided doses of from one. to six times daily. Children, geriatric patients and debilitated patientsfmay require quantities as low as 220 mg. of theactivecompound per unit dose, whereas those with the more severe pathologic entities may require as muchas 1.75. gm. of active'co'mpound per unit dose. This concentration of active ingredient pertains to all of the pharmaceutical dosage forms. Whencholine salicylate-Silanox compound is administered to a human or animal either in the form of a capsule, tablet, granule, effervescent tablet or effervescent granule, then a prompt and rapid elevation of the blood level of salicylate ion will be observed without coincidental gastro-intestinal distress or gastric bleeding as is commonly known to occur after the administration of the conventional salicylate compound, i.e., sodium salicylate and aspirin.

What is claimed is:

1. Choline salicylate trimethylsilyl silicon dioxide.-

' 2. The compound of claim 1 comprising from 30 to 140 parts by weight of trimethylsilyl silicon dioxide for each parts by weight of choline salicylate.

3., A method for the preparation of the compound of claim 1 comprising the step of combining from 0.3 to

l.4 parts by weight of trimethylsilyl silicon dioxide for each part by weight of choline salicylate.

, 4. The method of claim.3 wherein the quantity of silanized silicon dioxide added is an equal part by weight for each part by weight of choline salicylate.

5. A method for the preparation of the compound of claim 1, comprising the steps of: 1

(a) suspending a choline salt selected from the grou consisting of choline chloride, choline bromide, choline iodide, choline sulfate, choline nitrate, choline citrate, choline carbonate, choline bicarbonate, choline formate, choline bisulfate, choline sulfite, choline bisulfite and choline acetate in an inert solvent selected from the group consisting of acetone, anhydrous ether, benzene, chloroform, petroleum ether and anhydrous alcohol of the formula ROH wherein R is an alkyl group selected from the group consisting of alkyl groups having from 1 to 4 carbon atoms in chain length;

'(b) adding an equimolar weight of a metallic salicylate salt selected from the group consisting of sodium salicylate, potassium salicylate, magnesium salicylate, strontium salicylate, zinc salicylate and aluminum salicylate;

(c) refluxing for a period of about 4 hours;

( 1) cooling and filtering; 1

(e) adding a quantity of silanized silicon dioxide of between 0.3 to 1.4 percent by weight of the weight of choline salicylate formed;

(f) stirring and setting aside overnight, and

(g) recovering the formed choline salicylate silanized silicon dioxide therefrom.

, 6. The method of claim 5 wherein the quantity of silanized silicon dioxide added is an equal part byweight of the Weight of choline salicylate formed.

. k References Cited Chemical Abstracts, 59, 1152921, (1963). Chemical Abstracts, 73, 20898j, (1970).

DANIEL B. WYMAN, Primary Examiner P. F. SHAVER, Assistant Examiner U.S. c1. X.R. 260-4483 3; 424-484 

